Synthesis of polysubstituted, functionalized quinolines through a metal-free domino process involving a C4-C3 functional group rearrangement

Article abstract of DOI:10.1021/ol300132e

4-Alkyl-1,2,3,4-tetrahydroquinolines bearing a 4-vinyl unit ending in an electron-withdrawing group were efficiently transformed into polysubstituted, C₃-functionalized quinolines upon heating in refluxing o-dichlorobenzene, in a domino reactio

Full text of DOI:10.1021/ol300132e

ORGANIC
LETTERS
2012
Vol. 14, No. 6
1402–1404
Synthesis of Polysubstituted,
Functionalized Quinolines through a
Metal-Free Domino Process Involving a
C4ÀC3 Functional Group Rearrangement
ꢀ
Pascual Ribelles, M. Teresa Ramos, and J. Carlos Menendez*
´
Departamento de Quımica Organica y Farmaceutica, Facultad de Farmacia,
Universidad Complutense, Plaza de Ramon y Cajal, s.n., 28040 Madrid, Spain
ꢀ
ꢀ
ꢀ
josecm@farm.ucm.es
Received January 18, 2012
ABSTRACT
4-Alkyl-1,2,3,4-tetrahydroquinolines bearing a 4-vinyl unit ending in an electron-withdrawing group were efficiently transformed into
polysubstituted, C3-functionalized quinolines upon heating in refluxing o-dichlorobenzene, in a domino reaction involving an unusual C4ÀC3
functional group rearrangement.
Quinoline is one of the most important nitrogen hetero-
cycles, being widespread in nature and present as a key
structural unit in a large number of families of bioactive
compounds.1 Although quinoline synthesis has been stud-
ied for more than a century,2,3 there is still a clear need for
versatile methods that give access to highly substituted
quinoline systems under environmentally benign condi-
tions. We report here a concise route that affords poly-
substituted, functionalized quinolines from simple, readily
available starting materials, having as the key step a new re-
arrangement of 4,4-disubstituted 1,2,3,4-tetrahydroquinoline
derivatives that transfers one of the C-4 substituents to
the C-3-position and thus allows aromatization to take
place. This rearrangement was planned to be initiated by
an intramolecular Michael reaction of an in situ generated
enamine onto Michael acceptor groups present at C-4.
The starting materials for our study came from the
InCl3-catalyzed Povarov-like4 imino DielsÀAlder reac-
tion between aromatic imines and R,β-unsaturated di-
methylhydrazones, acting as the dienophiles.5 This reac-
tion allowed the diastereoselective synthesis of 1,2,3,4-
tetrahydroquinolines6 1 bearing a dimethylhydrazono
group at the quaternary C-4 stereocenter, which were trans-
formed into the corresponding aldehydes 2 by hydrolysis.7
These aldehydes were then used as starting materials for the
preparation of compounds 3aÀl, containing a C4-vinyl unit
ending in an electron-withdrawing group via a variety of
olefination methods including WadsworthÀEmmons,
Henry, and Knoevenagel reactions (Scheme 1 and Table 1).
(1) For selected recent reviews, see: (a) Khan, M. T. H. Top.
Heterocycl. Chem. 2007, 11, 213. (b) Kaur, K.; Jain, M.; Reddy, R. P.;
Jain, R. Eur. J. Med. Chem. 2010, 45, 3245. (c) Bongarzone, S.;
Bolognesi, M. L. Expert Opin. Drug Discovery 2011, 6, 1. (d) Solomon,
V. R.; Lee, H. Curr. Med. Chem. 2011, 18, 1488.
(2) For a review of the traditional quinoline syntheses, see: Jones, G.,
Ed. Comprehensive Heterocyclic Chemistry II; Katritzky, A., Rees, C. W.,
Scriven, E. F. V., general editors; Pergamon Press: 1996; Vol. 5, Chapter 5.05,
p 167.
(4) For reviews of the Povarov reaction, see: (a) Glushkov, V. A.;
Tolstikov, A. G. Russ. Chem. Rev. 2008, 77, 137. (b) Kouznetsov, V. V.
Tetrahedron 2009, 65, 2721. (c) Bello, D.; Ramon, R.; Lavilla, R. Curr.
ꢀ
Org. Chem. 2010, 14, 332.
(5) (a) Sridharan, V.; Perumal, P. T.; Avendano, C.; Menendez, J. C.
~
ꢀ
ꢀ
Org. Biomol. Chem. 2007, 1351. (b) Sridharan, V.; Ribelles, P.; Estevez, V.;
ꢀ
Villacampa, M.; Ramos, M. T.; Perumal, P. T.; Menendez, J. C. Chem.;
Eur. J. 2012, DOI: 10.1002/chem.201103562.
(6) For a review of the chemistry of tetrahydroquinolines, see:
(3) For reviews of more recent methods, see: (a) Kouznetsov, V. V.;
ꢀ
Sridharan, V.; Suryavanshi, P.; Menendez, J. C. Chem. Rev. 2011, 111,
7157.
ꢀ
ꢀ
ꢀ
Vargas Mendez, L. Y.; Melendez Gomez, C. M. Curr. Org. Chem. 2005,
9, 141. (b) Madapa, S.; Tusi, Z.; Batra, S. Curr. Org. Chem. 2008, 12,
1116.
(7) Mino, T.; Fukui, S.; Yamashita, M. J. Org. Chem. 1997, 62, 734.
r
10.1021/ol300132e
Published on Web 02/08/2012
2012 American Chemical Society

Table 1. Results Obtained in the Synthesis of Starting Materials 3
entry
compd
R2
Y
Z
R4
R5
R6
R7
R8
yield 2(%)
yield 3 (%)
1
a
b
c
d
e
f
C6H5
H
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
COCH3
CN
Me
Me
Me
Me
Me
Me
Me
Et
H
OMe
OMe
Me
H
H
H
H
H
H
H
Me
H
H
H
H
H
87
89
87
93
84
96
82
80
86
81
72
70
86
85
83
80
85
96
83
2
4-MeC6H4
4-MeOC6H4
4-ClC6H4
C6H5
H
H
H
H
H
H
H
H
H
H
CN
H
H
3
H
H
4
H
OMe
H
H
5
Me
OMe
H
Me
OMe
H
6
4-MeC6H4
C6H5
H
7
g
h
i
Me
8
C6H5
H
OMe
OMe
OMe
OMe
OMe
H
85
a
9
C6H5
Me
Me
Me
Me
H
H
a
a
a
10
11
12
j
C6H5
H
H
k
l
C6H5
NO2
H
H
C6H5
CN
H
H
a Compounds 3iÀl come from aldehyde 2a.
Scheme 1. Synthesis of Starting Materials 3
We next undertook the generation of an enamine func-
tion by dehydrogenation ofthe tetrahydroquinoline ring in
compounds 3, in order to examine its intramolecular
addition onto the C-4 vinyl chain. After some experimen-
tation, we discovered that both processes could be carried
out in a single operation by simply heating compounds 3 in
refluxing o-dichlorobenzene. This reaction afforded quin-
olines 4 in one step via an unprecedented C4 to C3 func-
tional group rearrangement.8 As shown in Figure 1, this
route gives access to a broad range of polysubstituted
quinolines bearing a functional group at C-3 and substit-
uents at their C-2, C-4, C-6, and C-8 positions. The yields
of the rearrangement step were normally good to excellent,
but the reaction failed to afford C-5 substituted quinolines
(reactions starting from 3e and 3f), probably for steric
reasons as will be discussed below.
Figure 1. Scope of the quinoline synthesis. Conditions: o-
Dichlorobenzene, reflux. Compound 4j was obtained as a 60/40
mixture of the corresponding E and Z diastereomers.
In order to rationalize these results, we propose the
domino mechanism summarized in Scheme 2, where the
starting material is first dehydrogenated by air under the
reaction conditions, affording intermediate A. An intra-
molecular addition of the enamine unit of A onto its
Michael acceptor portion (exemplified here by an R,β-
unsaturated ester) leads to the migration of this fragment
(8) Typical experimental procedure: A solution of the suitable com-
pound 3 (0.7À0.8 mmol) was refluxed in o-dichlorobenzene (5 mL) until
no starting material was detected by TLC. The reaction mixture was
allowed to reach room temperature and then evaporated to dryness. The
oily residue was purified by column chromatography eluting with
mixtures of petroleum etherÀAcOEt to give compounds 4.
Org. Lett., Vol. 14, No. 6, 2012
1403

reaction of C furnishes the aromatic quinoline derivatives
4. Steric compression between R5 and the substituents at
C-4 in intermediate B explains the failure of the reactions
starting from compounds 3e and 3f.
Scheme 2. Rationalization of the Formation of Compounds 4
In conclusion, we have developed a unique route to
highly substituted, functionalized quinolines based on an
unprecedented domino sequence from tetrahydroquino-
lines involving transfer of a three-carbon unit from C-4 to
C-3, thus leading to a further increase in the structural
diversity of accessible substituted quinolines.
This protocol has the additional advantage of requiring
only very simple starting materials and reagents and not
involving the use of metal catalysts.
Acknowledgment. We thank MICINN (Grant CTQ2009-
12320-BQU) and UCM (Grant GR35/10-A-920234) for
financial support.
Supporting Information Available. Experimental data
and spectra of all compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
of the molecule from C-4 to C-3 via the generation and
subsequent opening of an unstable cyclopropane intermedi-
ate B, leading to C. Finally, a second dehydrogenation
The authors declare no competing financial interest.
1404
Org. Lett., Vol. 14, No. 6, 2012